Compared to inorganic selenium, synthetic organic selenium compounds offer greater promise for the chemoprevention of cancer, in that their chemical structures can be tailored to provide maximum efficacy with minimal toxicity. To design more effective organoselenium compounds, it is necessary to understand their efficacy, mode of action, and structure and activity relationships. The long term objective of the Collaborative Chemoprevention Project is to elucidate the role of novel organoselenium compounds that are less toxic but effective as chemopreventive agents in colon carcinogenesis. Specifically, the overall project aims to test p-methoxybenzeneselenol (MBS) and benzylselenocyanate (BSC), that have been shown to inhibit colon tumor incidence in animal models, for toxicologic and pharmacologic properties. It also aims to investigate the efficacy of various levels of MBS and BSC fed during initiation and post-initiation phases of colon carcinogenesis induced by a variety of chemical carcinogens and to identify the mechanism of action of these organoselenium compounds during the initiation and post-initiation stages of colon carcinogenesis. In addition, we propose to determine whether the parent organoselenium compounds or one of their metabolites are responsible for their inhibitory activity. It is also proposed to modify the structures of BSC and MBS in order to enhance their inhibitory activity and reduce their toxicity and to test the most active and lease toxic compounds or inhibitors of colon carcinogenesis. Thus, the data base obtained from the proposed project could provide the basis for further studies to the rational design of chemopreventive compounds of greater effectiveness and help to translate laboratory findings to the human setting.